Administration of a Large Nesiritide Bolus Dose in a Pediatric Patient: Case Report and Review of Nesiritide Use in Pediatrics Brady S. Moffett, Pharm.D., John L. Jefferies, M.D., M.P.H., Jack F. Price, M.D., Sarah Clunie, R.N., Susan Denfield, M.D., William J. Dreyer, M.D., and Jeffrey A. Towbin, M.D. Nesiritide (recombinant B-type natriuretic peptide) is often given for symptomatic relief of acute decompensated heart failure in adults. The literature describing the safety or efficacy of nesiritide in children is minimal, and we know of no data that describe the effects of a nesiritide overdose in adults or children. A 3-year-old, 10.9-kg girl was admitted to the pediatric intensive care unit with the diagnosis of dilated cardiomyopathy and acute decompensated heart failure. She received several vasoactive infusions during her admission, including nesiritide. On hospital day 47 (day 45 of nesiritide therapy), the patient received an 18-fold overdose of nesiritide, with no hemodynamic, cardiac, or renal sequelae. She subsequently underwent successful cardiac transplantation. The nesiritide treatment duration was longer for this patient than the 45 days previously reported in a pediatric patient. No hemodynamic instability or cardiac or renal sequelae were associated with the large, inadvertent bolus in our patient. This case report demonstrates the lack of adverse events in a pediatric patient administered nesiritide beyond the recommended dosing parameters. Increased vigilance is always advised when administering drugs not commonly given to pediatric patients. Key Words: nesiritide, pediatric patients, overdose, dilated cardiomyopathy. (Pharmacotherapy 2006;26(2):277–280) Nesiritide is a common short-term therapy administered for treatment of acute decompensated heart failure in adults. 1, 2 However, experience with nesiritide as therapy for pediatric patients is very limited. We describe long-term nesiritide therapy in a child who also received an unintentional bolus of the drug. Case Report A 3-year-old, 10.9-kg, African-American girl From the Department of Pharmacy, Texas Children’s Hospital (Dr. Moffett), and the Lillie Frank Abercrombie Section of Cardiology, Department of Pediatrics, Baylor College of Medicine (Drs. Jefferies, Price, Denfield, Dreyer, and Towbin, and Ms. Clunie), Houston, Texas. Address reprint requests to Brady S. Moffett, Pharm.D., Department of Pharmacy, Texas Children’s Hospital, 6621 Fannin Street, MC 2-2510, Houston, TX 77030; e-mail:
[email protected].
with a history of dilated cardiomyopathy was admitted to our institution with signs and symptoms of acute decompensated heart failure. At the time of her transfer from another hospital, the patient was receiving intravenous inotropic therapy with milrinone and dobutamine. Her drug therapy at home consisted of digoxin, captopril, spironolactone, and furosemide. Her plasma B-type natriuretic peptide whole blood concentration, obtained on day 1 at our hospital, was 3100 pg/ml (normal range 0–100 pg/ml), indicating decompensated heart failure. The decision was made to treat the patient’s acute decompensation as bridge therapy to heart transplantation. On hospital day 2, a nesiritide infusion was started at 0.01 µg/kg/minute, with no bolus dose, and titrated to 0.02 µg/kg/minute over the next
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PHARMACOTHERAPY Volume 26, Number 2, 2006 Table 1. Hemodynamic Parameters Before Nesiritide Bolus Dose Administration No. of Days Systolic Diastolic Mean Arterial Before Bolus Blood Pressure Blood Pressure Pressure Heart Rate Administered (mm Hg) (mm Hg) (mm Hg) (beats/min) 3 90–65 55–35 70–42 125–205 2 105–70 72–40 90–45 110–180 1 105–65 62–38 85–50 120–160
24 hours. The patient responded with a brisk diuresis, from 2.6 to 3.7 ml/kg/hour; her serum creatinine concentration remained stable at 0.4 mg/dl (normal range 0.2–1.2 mg/dl). After the initial response to nesiritide, her urine output decreased over the next 24 hours to 1.5 ml/kg/hour, and her serum creatinine concentration increased to 0.7 mg/dl. The nesiritide infusion was increased to 0.03 µg/kg/minute. The patient’s urine output subsequently increased to 3.9 ml/kg/hour, and her serum creatinine concentration decreased to 0.3 mg/dl. The nesiritide infusion was then maintained at 0.03 µg/kg/minute to promote afterload reduction, maintain cardiac output, and achieve a negative fluid balance. The nesiritide dosage was increased again 18 days later in response to a positive fluid balance and a decrease in urine output to 1.9 ml/kg/hour; serum creatinine concentration increased to 0.7 mg/dl. The patient’s urine output subsequently increased to 3.4 ml/kg/hour within 4 days after the nesiritide dosage was increased to 0.04 µg/kg/minute; her serum creatinine concentration decreased from 0.7 to 0.6 mg/dl. Throughout her hospital course, other inotropic and vasoactive drug therapies were discontinued, started, or titrated to maintain cardiac output without significant change in blood pressure. The increase in urine output was believed to be directly related to the increase in nesiritide dosage, and not related to any changes in inotropic or vasopressor support. On hospital day 47 (day 45 of nesiritide therapy) at 2:00 A.M., the patient inadvertently received, within 1 hour, the entire contents of a 60-ml syringe containing nesiritide 360 µg, which had been intended for infusion over 24 hours. This was the equivalent of a bolus dose of approximately 36 µg/kg. When the bolus dose was given, the patient was also receiving dopamine 3 µg/kg/minute, milrinone 0.6 µg/kg/minute, calcium chloride 2.5 mg/kg/hour, vasopressin 0.01 U/kg/hour, and nesiritide 0.04 µg/kg/minute, as well as captopril 0.3 mg/kg/day,
Central Venous Urine Pressure Output (mm Hg) (ml/24 hrs) 1–11 609 -12–11 958 -2–11 635
metolazone 1 mg/kg/day, ethacrynic acid 1 mg/kg/day, furosemide 1 mg/kg/day, and ranitidine. She was also receiving cefotaxime and vancomycin for possible sepsis. The drug error was discovered approximately 12 hours after administration of the bolus, at which time the concurrent nesiritide infusion was discontinued. Neither symptoms nor hypotension developed, and neither inotropic nor vasopressor support was escalated in the 12 hours after the unintentional bolus administration. Also, no clinically significant changes occurred in the patient’s urine output or renal function (Tables 1 and 2). Her serum creatinine concentration did not change significantly over the next 2 days (0.4 and 0.5 mg/dl). In addition, no arrhythmia occurred with the nesiritide bolus. The patient eventually underwent heart transplantation and was discharged from the hospital. Approximately 1 year later, her serum creatinine concentration was 0.4 mg/dl. Discussion Nesiritide is the recombinant form of the endogenously secreted B-type natriuretic peptide, which is secreted by the ventricular myocardium under conditions of ventricular volume or pressure load and results in afterload reduction, vasodilation, and diuresis. Nesiritide has reduced cardiac remodeling effects by decreasing myocyte hypertrophy, renin and aldosterone secretion, and endogenous sympathetic activity.3 Nesiritide is indicated for treatment of acute decompensated heart failure in adults who experience dyspnea at rest or with minimal activity. The recommended nesiritide dosing scheme is a 2-µg/kg bolus followed by an initial infusion of 0.01 µg/kg/minute, which may be titrated up by 0.005 µg/kg/minute every 3 hours to a maximum of 0.03 µg/kg/minute. Current dosing recommendations limit nesiritide to a 72hour infusion.4 Literature detailing nesiritide therapy in pediatric patients is scarce. At the time of this
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NESIRITIDE OVERDOSE IN A PEDIATRIC PATIENT Moffett et al Table 2. Hemodynamic Parameters After Nesiritide Bolus Dose Administration on Day 45 of Therapy Systolic Diastolic Mean Arterial Central Venous Urine Blood Pressure Blood Pressure Pressure Heart Rate Pressure Output Time (mm Hg) (mm Hg) (mm Hg) (beats/min) (mm Hg) (ml) A.M. 2:00 80 60 65 125 5 — 3:00 80 45 65 120 6 — 4:00 100 45 65 120 7 170 5:00 NR NR NR 150 7 — 6:00 80 50 62 145 2 — 7:00 90 55 68 135 NR — 8:00 95 55 65 130 0 — 9:00 95 55 65 145 2 — 10:00 95 45 58 130 0 — 11:00 90 45 58 135 0 — P.M. 12:00 1:00 2:00
105 85 95
50 55 65
75 70 75
155 135 150
3 2 6
150 284
NR = not reported.
Table 3. Summary of Pediatric Patients Who Have Received Nesiritide Therapy Nesiritide No. of Dosage Duration Disorder or Procedure Patients (µg/kg/min) (days) Effects Congenital heart disease, 6 0.005–0.02 10.6 ± 4.1 ↑ urine output, no hypotension dilated cardiomyopathy 1 (mean ± SD) (awaiting transplant) Trauma, closed head injury 2 0.01–0.03 5.8, 4.6 ↑ urine output (1 patient), ↓ diuretic use, ↑ peripheral perfusion, ↑ mixed venous oxygen saturation Coarctation repair 1 0.01–0.03 2.5 Control of hypertension, ↑ urine output, (postoperative) ↑ peripheral perfusion 1 0.005 10 ↑ urine output, improvement in Coarctation repair, ventral septal defect closure echocardiographic indexes (postoperative) Mitral valve repair 1 0.005–0.01 6 ↑ urine output, ↓ diuretic use 1 0.01–0.03 7.6 ↓ diuretic use, ↑ peripheral perfusion, Mitral valve replacement ↑ mixed venous oxygen saturation Diastolic dysfunction 1 1 µg/kg (bolus), 3 ↑ urine output, ↓ BUN and Scr, ↓ dyspnea (after orthotopic heart then 0.01 transplant) Failed Fontan operation 1 1 µg/kg (bolus), 3 ↑ urine output, ↓ BUN and Scr, ↓ dyspnea then 0.01 Septic shock 1 0.01–0.02 2 ↑ urine output, ↑ peripheral perfusion, dobutamine discontinued Infants receiving ECMO 2 0.01–0.09 5, 9 ↓ afterload, ↓ use of sodium nitroprusside (1 patient), ↑ urine output BUN = blood urea nitrogen concentration; Scr = serum creatinine concentration; ECMO = extracorporeal membrane oxygenation. From references 5–9.
writing, there were a total of 18 pediatric patients reported in the literature who had received nesiritide (Table 3).5–9 Most of these patients did not receive a bolus dose before the infusion was started, and they were treated for more than 72
hours. Although data are limited, nesiritide therapy is generally considered safe for pediatric patients at dosages similar to those in adult patients.10 A bolus dose of nesiritide was not planned for
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our patient due to concerns about hypotension and the patient’s tenuous condition. Adult patients who did not receive a bolus dose have demonstrated hemodynamic improvement, diuresis, and natriuresis within 30–60 minutes of the start of their infusion. 4 In addition, the previous reports of nesiritide therapy in pediatric patients have shown beneficial results without administration of a bolus dose.5–9 We believed a bolus dose of nesiritide would have put the patient at undue risk for an adverse event, compared with starting the infusion at 0.01 µg/kg/minute. Our patient received nesiritide for a total of 45 days, which is much longer than the recommended length of treatment for adults with acute decompensated heart failure. Due to this girl’s tenuous status and the number of pharmacologic interventions necessary to maintain adequate cardiac output, we felt the nesiritide infusion should be maintained until she received a heart transplant. In addition to the initial diuresis and natriuresis, nesiritide has other mechanisms that could be beneficial to our patient. This drug has demonstrated potential antifibrotic and antiproliferative effects on the myocardium and can decrease myocyte hypertrophy. 3 It reduces afterload through vasodilation, which can reduce exogenous inotrope requirements and limit myocardial oxygen demand. These effects are all beneficial for a patient receiving bridge therapy to heart transplantation, and they serve as a rationale for extended nesiritide therapy. Our patient received 18 times the usual bolus dose used in adults after receiving a nesiritide infusion for an extended time with no adverse hemodynamic or physical effects. She also was receiving inotropes (calcium chloride, milrinone, and dopamine) and a vasopressor (vasopressin) at the time of the drug error, which may have prevented a hypotensive episode. It is unlikely that the patient developed tachyphylaxis against nesiritide, since previous reports have shown a lack of this effect when compared with other drugs, such as nitrates.11 Recent reports of increased renal insufficiency and mortality after nesiritide therapy have been published, including a MedWatch alert from the Food and Drug Administration.12–14 Of note, the serum creatinine concentration did not increase significantly in our patient up to 48 hours after she received the large bolus dose of nesiritide, and her serum creatinine concentration remained stable up to 1 year afterward.
Investigation indicated that unfamiliarity with nesiritide may have been the primary contributing factor to the drug error. Nesiritide is not commonly administered in pediatric patients and was not on the formulary at the time it was administered. To prevent further drug incidents, more education about nesiritide was provided, and the drug was added to our hospital formulary, with subsequent institutional guidelines for its therapeutic use. Conclusion A large bolus dose of nesiritide was administered in error to a 3-year-old girl with no cardiac, hemodynamic, or renal sequelae. She may have tolerated the large dose due to concomitant therapy with other inotropic and vasopressor drugs. However, increased vigilance is always advised when administering drugs not commonly given to pediatric patients. References 1. Yancy CW, Saltzberg MT, Berkowitz RL, et al. Safety and feasibility of using serial infusions of nesiritide for heart failure in an outpatient setting (from the FUSION I trial). Am J Cardiol 2004;94:595–601. 2. Publication Committee for the VMAC Investigators (Vasodilatation in the Management of Acute CHF). Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA 2002;287:1531–40. 3. Zineh I, Schofield RS, Johnson JA. The evolving role of nesiritide in advanced or decompensated heart failure. Pharmacotherapy 2003;23:1266–80. 4. Scios, Inc. Natrecor (nesiritide) package insert. Fremont, CA; 2004. 5. Sehra R, Underwood K. Nesiritide improves urine output in severely ill pediatric patients awaiting heart transplant without severe hypotension [abstr]. J Card Fail 2003;5:254. 6. Marshall J, Berkenbosch JW, Russo P, Tobias JD. Preliminary experience with nesiritide in the pediatric population. J Intensive Care Med 2004;19:164–70. 7. Simsic JM, Reddy VS, Kanter KR, Kirshbom PM, Forbess JM. Use of nesiritide (human B-type natriuretic peptide) in infants following cardiac surgery. Pediatr Cardiol 2004;25:668–70. 8. Feingold B, Law YM. Use of nesiritide in pediatric patients with congestive heart failure. J Heart Lung Transplant 2004;23:1455–9. 9. Smith T, Rosen DA, Russo P, et al. Nesiritide during extracorporeal membrane oxygenation. Paediatr Anaesth 2005;15:152–7. 10. Schamberger MS. Is there a use for nesiritide in pediatric patients? J Intensive Care Med 2004;19:171–3. 11. Maisel AS. Nesiritide: a new therapy for the treatment of heart failure. Cardiovasc Toxicol 2003;3:37–42. 12. Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term risk of death after treatment with nesiritide for decompensated heart failure. JAMA 2005;293:1900–5. 13. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 2005;111: 1487–91. 14. Food and Drug Administration. MedWatch program. Natrecor (nesiritide). Available from http://www.fda.gov/medwatch/ SAFETY/2005/safety05.htm#natrecor. Accessed July 26, 2005.
